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      Creating the Next Generation of Translational Geroscientists

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          Abstract

          Advances in understanding fundamental processes of aging have led to a variety of investigational therapies to delay or prevent age‐related diseases and conditions. These geroscience therapeutics hold the promise of revolutionizing medical care of older adults by treating the complex syndromes of aging and preserving health and independence. A crucial bottleneck is the study of geroscience therapeutics in early‐stage, first‐in‐human, or proof‐of‐concept clinical trials. There is a limited pool of clinical investigators with the combination of knowledge and skills at the interface of clinical research, care of older adults, and aging biology needed to successfully design, fund, and implement geroscience trials. Current training pipelines are insufficient to meet the need. The sixth retreat of the National Institute on Aging R24 Geroscience Network brought together basic scientists, gerontologists, clinicians, and clinical researchers from the United States and Europe to discuss how to identify, recruit, and train investigators who can perform early‐stage clinical trials in geroscience. We present herein the group's consensus on necessary subject domains and competencies, identification of candidate learners, credentialing learners, and the efficient and rapid implementation of training programs. Foundations and funding agencies have crucial roles to play in catalyzing the development of these programs. Geriatrician investigators are indispensable but cannot meet the need alone. Translational geroscience training programs can create a cadre of groundbreaking investigators from a variety of backgrounds and foster institutional cultures supportive of multidisciplinary translational aging research to turn innovative ideas into transformative therapeutics that can improve the health and independence of older adults. J Am Geriatr Soc 67:1934–1939, 2019

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          Most cited references11

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          Strategies and Challenges in Clinical Trials Targeting Human Aging

          Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use. We review the evidence that some drugs already in clinical use may target fundamental aging processes. We discuss the design principles of clinical trials to test such interventions in humans, including study populations, interventions, and outcomes. As examples, we offer several scenarios for potential clinical trials centered on the concepts of health span (delayed multimorbidity and functional decline) and resilience (response to or recovery from an acute health stress). Finally, we describe how this discussion helped inform the design of the proposed Targeting Aging with Metformin study.
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            Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

            Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions—a concept dubbed the “geroscience hypothesis.” Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes.
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              Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience

              Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains. A particularly sensitive metric of health is the ability to respond to, and recover, from stress. Therefore, the Network also considered stresses of human relevance that could be implemented in mouse models to assess frailty and resilience. Mouse models already exist for responses to forced immobility, cancer chemotherapy, infectious diseases, dietary challenges, and surgical stress, and it was felt that these could be employed to determine whether putative senescence-retarding interventions increased and extended organismal robustness. The Network discussed challenges in modeling age-related human chronic diseases and concluded that more attention needs to be paid to developing disease models with later age of onset, models of co- and multimorbidity, diversifying the strains and sexes commonly used in aging research, and considering additional species.
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                Author and article information

                Contributors
                @GeriSciDoc
                @JLSokoloski
                @StevenAustad
                @george_kuchel
                pignolo.robert@mayo.edu
                Journal
                J Am Geriatr Soc
                J Am Geriatr Soc
                10.1111/(ISSN)1532-5415
                JGS
                Journal of the American Geriatrics Society
                John Wiley & Sons, Inc. (Hoboken, USA )
                0002-8614
                1532-5415
                09 July 2019
                September 2019
                : 67
                : 9 ( doiID: 10.1111/jgs.v67.9 )
                : 1934-1939
                Affiliations
                [ 1 ] Buck Institute for Research on Aging, and University of California San Francisco Division of Geriatrics Novato, California
                [ 2 ] Robert and Arlene Kogod Center on Aging and the Division of Geriatric Medicine and Gerontology, Department of Medicine Mayo Clinic Rochester Minnesota
                [ 3 ] Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Institute on the Biology of Aging and Metabolism Minneapolis Minnesota
                [ 4 ] Division of Gerontology, Department of Medicine University of Washington Seattle Washington
                [ 5 ] Department of Geriatrics College of Medicine–University of Arkansas Medical Sciences Little Rock Arkansas
                [ 6 ] Department of Biology University of Alabama at Birmingham Birmingham Alabama
                [ 7 ] Department of Medicine Albert Einstein College of Medicine Bronx New York
                [ 8 ] Department of Genetics Albert Einstein College of Medicine Bronx New York
                [ 9 ] Institute for Aging Research, Albert Einstein College of Medicine Bronx New York
                [ 10 ] Duke University Medical Center Durham North Carolina
                [ 11 ] UConn Center on Aging University of Connecticut Farmington Connecticut
                Author notes
                [*] [* ]Address correspondence to Robert J. Pignolo, MD, PhD, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 1st St SW, Rochester, MN 55905. E‐mail: pignolo.robert@ 123456mayo.edu
                Article
                JGS16055
                10.1111/jgs.16055
                6771814
                31287934
                5bf44f27-72d5-41ef-97b7-a87e0da7b2eb
                © 2019 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 08 November 2018
                : 05 May 2019
                : 18 May 2019
                Page count
                Figures: 2, Tables: 0, Pages: 6, Words: 4589
                Funding
                Funded by: National Institutes of Health
                Award ID: R24 AG44396
                Award ID: R33 AG061456
                Categories
                Education and Training
                Education and Training
                Custom metadata
                2.0
                jgs16055
                September 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:01.10.2019

                Geriatric medicine
                Geriatric medicine

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